Phase II Study Suggests Promise of Intermittent Chemotherapy Plus Continuous Cetuximab in Advanced KRAS Wild-Type Colorectal Cancer
In a phase II study (COIN-B) reported in The Lancet Oncology, Wasan et al examined the addition of continuous or intermittent cetuximab (Erbitux) to intermittent chemotherapy in previously untreated advanced KRAS wild-type colorectal cancer. Continuous cetuximab appeared to be associated with advantages over intermittent administration.
As noted by the investigators, the trial is one of a series in patients with noncurable advanced colorectal cancer exploring strategies to improve combinations and sequences of cytotoxic chemotherapy, targeted treatments, and planned maintenance and interruptions with the aim of reducing toxicity and improving quality of life without reducing survival.
Study Details
In this open-label exploratory trial conducted at 30 hospitals in the United Kingdom and 1 in Cyprus, 226 patients with no previous chemotherapy for metastatic disease were randomly assigned to receive intermittent FOLFOX (leucovorin and oxaliplatin followed by bolus and infused fluorouracil) plus intermittent cetuximab or continuous cetuximab. Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, followed by interruption or continuation of weekly cetuximab. At progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance of cetuximab, respectively.
The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. The trial was not powered for comparison between the treatment groups.
The trial was designed before KRAS mutation was identified as predictor of resistance to EGFR inhibitors. It was suspended in May 2008 and restarted in January 2009 with a protocol change to include prospective KRAS mutation analysis before randomization and to include only KRAS wild-type patients. The KRAS status of already enrolled patients was assessed while the trial was suspended, and BRAF/NRAS status was retrospectively assessed.
Analysis in KRAS Wild-Type Patients
The current report includes results for only the 169 patients with KRAS wild-type disease, including 78 (46%) receiving intermittent cetuximab and 91 (54%) receiving continuous cetuximab. There were imbalances between these two treatment groups. More patients in the continuous-cetuximab group were KRAS wild-type when tested retrospectively (37 vs 25), were elderly (13% vs 6% aged ≥ 75 years), had WHO performance score of 2 (10% vs 6%), had BRAF mutations (18% vs 10%), and had primary colon (vs rectal) cancer (81% vs 68%).
Improved Outcomes With Continuous Cetuximab
Of the 169 patients, 64 in the intermittent-cetuximab group and 66 in the continuous group were included in the primary analysis. Ten-month failure-free survival was 50% (lower bound of 95% confidence interval [CI] = 39%) in the intermittent group vs 52% (lower bound of 95% CI = 41%) in the continuous group, median failure-free survival was 12.2 (95% CI = 8.8–15.6) vs 14.3 months (95% CI = 10.7–20.4), median progression-free survival from week 12 was 3.1 (95% CI = 2.8–4.7) vs 5.8 months (95% CI = 4.9–8.6), and median overall survival was 16.8 (95% CI = 14.5–22.6) vs 22.2 months (95% CI = 18.4–28.9).
Among 77 patients restarting treatment after a chemotherapy-free interval, 44 were in the intermittent-cetuximab group and 33 were in the continuous-cetuximab group. The median chemotherapy-free interval was 3.7 months vs 5.5 months. Among patients surviving ≥ 24 weeks, the disease control rate was 22% vs 32%.
Toxicity
The most common grade 3 or 4 adverse events in the total KRAS wild-type intermittent- vs continuous-cetuximab groups were skin rash (27% vs 22%), neutropenia (29% vs 33%), diarrhea (18% vs25%), and lethargy (26% vs 21%). Grade 3 or 4 hypersensitivity reactions occurred in three patients in the intermittent-cetuximab group, including in one at reintroduction of treatment.
The investigators concluded, “Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.”
Angela M. Meade, DPhil, of MRC Clinical Trials Unit at University College London, is the corresponding author for The Lancet Oncology article.
The study was funded by the UK Medical Research Council and Merck KGaA. For full disclosures of the study authors, visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
